pISSN 2287-2728 eISSN 2287-285X
Original Article
http://dx.doi.org/10.3350/cmh.2016.22.1.152 Clinical and Molecular Hepatology 2016;22:152-159
Comparison of tenofovir plus lamivudine versus tenofovir monotherapy in patients with lamivudineresistant chronic hepatitis B Chan Ho Park, Seok Won Jung, Jung Woo Shin, Mi Ae Bae, Yoon Im Lee, Yong Tae Park, Hwa Sik Chung, and Neung Hwa Park Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
Background/Aims: Tenofovir disoproxil fumarate (TDF) exhibits similar antiviral efficacy against treatment-naïve and lamivudine (LAM)-resistant chronic hepatitis B (CHB). However, there are few clinical reports on the antiviral effects of TDF–LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB. Methods: We investigated the antiviral efficacy of TDF monotherapy vs. TDF–LAM combination therapy in 103 patients with LAM-resistant CHB. Results: The study subjects were treated with TDF alone (n=40) or TDF–LAM combination therapy (n=63) for ≥6 months. The patients had previously been treated with TDF-based rescue therapy for a median of 30.0 months (range, 8–36 months). A virologic response (VR) was achieved in 99 patients (96.1%): 95.0% (38/40) of patients in the TDF monotherapy group and 96.8% (61/63) of patients in the TDF–LAM combination therapy group. The VR rates were not significantly different between the TDF monotherapy and TDF–LAM combination therapy groups (88.9 vs. 87.3% at month 12, and 94.4 vs. 93.7% at month 24, log-rank P=0.652). Univariate and multivariate analyses revealed that none of the pretreatment factors were significantly associated with VR. Conclusions: TDF monotherapy was as effective as TDF–LAM combination therapy for maintaining viral suppression in the vast majority of patients with LAM-resistant CHB, which suggests that TDF add-on therapy with LAM is unnecessary. (Clin Mol Hepatol 2016;22:152-159) Keywords: Tenofovir; Lamivudine; Resistance; Chronic hepatitis B
INTRODUCTION Hepatitis B virus (HBV) infection is a serious public health problem worldwide, with an estimated 2 billion infections, and a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC).1 Higher levels of HBV DNA are associated with an
increased risk for hepatocellular carcinoma (HCC) and cirrhosis.2,3 Thus, lowering of HBV DNA levels from the highest levels has been linked with a reduction in risk of both cirrhosis and HCC.4-7 Therefore, the goal of therapy in patients with chronic hepatitis B (CHB) is rapid and sustained viral suppression. Nucleos(t)ide analogues (NAs) as an important class of antiviral
Abbreviations:
Corresponding author : Neung Hwa Park
ADV, adefovir; AE, adverse event; CHB, chronic hepatitis B; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LAM, lamivudine; PCR-RFLP, polymerase chain reactionrestriction fragment length polymorphism; PVR, partial virologic response; RFMP, restriction fragment mass polymorphism; TDF, tenofovir disoproxil fumarate; VBT, virologic breakthrough; VR, virologic response
Department of Internal Medicine, Ulsan University Hospital, 877 Bangeojinsunhwando-ro, Dong-gu, Ulsan 44033, Korea Tel: +82-52-250-8845, Fax: +82-52-250-7048 E-mail: [email protected]
Received : Sep. 17, 2015 / Revised : Jan. 21, 2016 / Accepted : Feb. 11, 2016 Copyright © 2016 by The Korean Association for the Study of the Liver This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Chan Ho Park, et al. TDF-based therapy in LAM-resistant CHB
drugs have changed the treatment paradigm and prognosis of CHB. Lamivudine (LAM), the first oral antiviral agent approved to treat HBV, is safe and well tolerated, even in patients with decompensated liver cirrhosis.8 However, long-term use of NAs inevitably leads to the development of resistant HBV mutants and viral breakthrough. Resistance to LAM emerges in approximately 20% of patients after 1 year and in 70% of patients after 5 years of treatment.9 Continued treatment with LAM monotherapy in patients with LAM-resistant CHB is not recommended due to liver disease progression, including worsening of fibrosis and cirrhosis, and selection of secondary mutations.10 In addition, an increasing number of patients experience multiple NAs treatment failures, especially when they are sequentially treated with NAs that have low genetic barrier such as LAM and ADV.11-13 Therefore, for CHB patients with LAM resistance, current international guidelines recommend switching to tenofovir disoproxil fumarate (TDF), or adding on TDF.14,15 TDF achieved high rates of virologic suppression, with no development of genotypic resistance reported so far.16 TDF is recommended as first-line therapy in patients with CHB.14,15 It is also recommended for patients who have developed resistance to LAM. TDF is active in vitro against both wild-type and LAM-resistant HBV.17 Several studies have shown that the efficacy of TDF monotherapy for treating of patients with LAM-resistant CHB is currently limited to small case series or retrospective clinic-based studies.18-21 In addition, recent data show that TDF rescue therapy with LAM or emtricitabine retains significant activity for patients with LAM-resistant HBV.22-24 Fung et al. studied the efficacy of TDF/emtricitabine combination therapy compared to that of TDF monotherapy in patients with LAM-resistant CHB.25 That study showed that TDF monotherapy was as effective as the combination of TDF/emtricitabine in patients with LAM-resistant CHB. However, clinical experience with the antiviral effect of TDF-LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB is limited. In this study, we evaluated the efficacy of TDF-LAM combination therapy compared to that of TDF monotherapy in patients who developed resistance to LAM. We also determined patient-dependent or laboratory variables that predicted VR.
PATIENTS AND METHODS Patient population We reviewed the electronic medical records of patients with http://www.e-cmh.org
LAM-resistant CHB and who were treated with TDF-based rescue therapy for at least 6 months. A total of 103 patients were treated with TDF alone or a LAM combination by clinician or patient choice from December 2012 to November 2015. The study subjects were treated with TDF alone (n=40) or a TDF-LAM combination (n=63) for ≥ 6 months. All patients had hepatitis B surface antigen (HBsAg) and HBV DNA in serum for at least 6 months before the start of LAM therapy. Patients with impaired renal function (serum creatinine > 1.5 mg/dL), antibodies to hepatitis C virus, antibodies to HIV, or autoimmune hepatitis were excluded. Additional criteria for exclusion were pregnancy, lactation, and alcohol abuse (> 40 g/day ethanol). Diagnoses of chronic hepatitis and liver cirrhosis were based on liver biopsy features or on clinical, laboratory, and ultrasound data. The diagnosis of CHB was based on histological examination for 16 patients. The remaining 87 patients were clinically diagnosed. Written informed consent was obtained from all patients participating in this study. This research was approved by the Institutional Review Board at the Ulsan University Hospital.
Laboratory measurements Liver and kidney function tests were performed every 3 months during TDF rescue therapy. HBV DNA levels were quantified using the COBAS TaqMan HBV test (Roche, Branchburg, NJ, USA), which has a lower detection limit of 12 IU/mL (60 copies/mL). Specific HBV genotypes were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of the surface gene of HBV genome. The two fragments of HBV genome between nucleotide positions 2823 and 2845 and 61 and 80 were amplified using PCR, and the products were treated with restriction enzymes. Genotypic resistance to LAM was tested by restriction fragment mass polymorphism (RFMP; Genematrix, Seongnam-si, Gyeonggi, Korea assay). The RFMP assay can detect 100 copies of HBV genome per milliliter. Patients underwent surveillance for HCC every 6 months, and serial abdominal ultrasound and serum a-fetoprotein measurements were performed.
Definitions Virologic response (VR) was defined as the absence of serum HBV DNA by PCR assay (< 12 IU/mL) on two consecutive measurements during TDF treatment. HBeAg seroconversion was defined as the loss of HBeAg accompanied by detection of anti-HBe
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and the absence of serum HBV DNA during treatment. Partial virologic response (PVR) was defined as a decrease in HBV DNA of
Table 1. Baseline characteristics of the studied patients (n=103)
> 1 log10 IU/mL but detectable HBV DNA after 6 months of TDFbased rescue therapy. Virologic breakthrough (VBT) was defined as a > 1 log10 IU/mL increase in serum HBV DNA from the nadir on two consecutive measurements or on the last available measurement. Safety and tolerability were evaluated by the occurrence of adverse events (AEs), serious AEs, laboratory abnormalities, discontinuation of the study drug due to AEs, or death. Specific markers of renal abnormalities included confirmed (defined as two consecutive visits) increase in serum creatinine of at least 0.5 mg/dL above the baseline value, serum phosphorus values < 2 mg/dL, and creatinine clearance < 50 mL/min.
Sex (male/female)
51 (27-90) 79/24
Liver cirrhosis, n (%)
34 (33.0)
AST (IU/L)
27.0 (15-2,431)
ALT (IU/L)
30.0 (6-3,248)
HBV DNA (log10 IU/mL)
3.61 (1.41-8.23)
HBeAg positivity, n (%)
78 (75.7)
Duration of LAM therapy (months)
33 (7-151)
Duration of TDF therapy (months)
30 (8-36)
LAM resistant mutations L180M M204V, L180M M204I, L180M M204I/V, M204I, M204V
44, 19, 12, 26, 2
Continuous variables are expressed as medians with range. AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; LAM, lamivudine;TDF, tenofovir.
Statistical analysis Serum HBV DNA (IU/mL) levels were logarithmically transformed for analysis. Continuous variables were compared using Student’s t test, and categorical variables were compared using the χ2 test. The cumulative probability rates of clinical outcomes were calculated using the Kaplan–Meier method. To identify factors predictive of outcome among the baseline variables, the clinical outcome variables were compared using the χ2 test or univariate logistic regression. Multivariate analysis was carried out using a stepwise logistic regression model. All data were analyzed using the SPSS ver. 19.0 for Windows statistical package (SPSS Inc., Chicago, IL, USA). A two-tailed P -value < 0.05 was considered significant.
RESULTS Overall clinical outcomes of TDF-based therapy The baseline characteristics of the 103 patients with CHB are shown in Table 1. All patients were genotype C2. The patients had been treated with LAM for a median of 33.0 months (range, 7–151 months) prior to TDF-based rescue treatment. All patients had LAM-resistant CHB. The known genotypic LAM mutations, L180M M204V, L180M M204I, L180M M204I/V, M204I, and M204V were detected in 44, 19, 12, 26, and two patients, respectively. Thirty-four (33.0%) patients had liver cirrhosis. Seventy-eight (75.7%) patients were HBeAg positive. The median HBV DNA level prior to TDF-based treatment was 3.61 log10 IU/mL (range, 1.41–8.23 log10 IU/mL). Thirty-four (33.0%) patients had abnormal alanine aminotransferase (ALT) levels. The subjects
154
Age (year)
were treated with TDF alone (n=40) or the TDF-LAM combination (n=63) for ≥ 6 months. The patients had been treated with TDFbased rescue therapy for a median of 30.0 months (range, 8-36 months). Mean pre-treatment HBV DNA level in HBeAg-positive CHB patients was 3.80 ± 1.58 log10 IU/mL, and it was 4.38 ± 1.51 log10 IU/mL in HBeAg-negative CHB patients. Mean pre-treatment HBV DNA level in HBeAg-negative CHB patients was similar to that in HBeAg-positive CHB patients (P =0.109). Among the 34 patients with elevated ALT levels at baseline, ALT levels were normalized in 31 patients (91.2%) during TDF-based treatment. VR was achieved in 99 patients (96.1%) during TDF-based rescue therapy. The cumulative rates of VR at 6, 12, and 24 months were 77.7%, 87.8%, and 93.9%, respectively. During TDF-based rescue therapy, 21 (20.4%) patients had PVR. Among the 78 HBeAgpositive patients, seven (9.0%) patients achieved HBeAg seroconversion during TDF-based treatment. However, no patient lost serum HBsAg during treatment. One patient in the TDF monotherapy group experienced VBT (increase in HBV DNA by 1 log10 IU/mL at 18 months of treatment) associated with documented nonadherence to medication (determined by review of medical and pharmacy records). This patient with VBT responded well to TDF monotherapy after continuation of treatment. No clinically significant AEs were observed during the TDFbased treatment. Mean creatinine level and estimated glomerular filtration rate did not change during the treatment period. Two patients (1.9%) had an increase in serum creatinine levels, but no patient had an increase in serum creatinine > 0.5 mg/dL. Mild hypophosphatemia (serum phosphorus < 2.7 mg/dL) was found in
http://dx.doi.org/10.3350/cmh.2016.22.1.152
http://www.e-cmh.org
Chan Ho Park, et al. TDF-based therapy in LAM-resistant CHB
only one patient without a change in serum creatinine.
Comparison of clinical outcomes between the TDFLAM combination and TDF monotherapy groups The baseline characteristics of the TDF monotherapy (n=40) and TDF-LAM combination groups (n=63) are shown in Table 2. There was no significant difference between the two groups except for baseline HBV DNA levels and HBeAg positivity. The patients in the TDF monotherapy group had significantly higher HBV DNA levels than the patients in the TDF-LAM combination therapy group (P
Original Article
http://dx.doi.org/10.3350/cmh.2016.22.1.152 Clinical and Molecular Hepatology 2016;22:152-159
Comparison of tenofovir plus lamivudine versus tenofovir monotherapy in patients with lamivudineresistant chronic hepatitis B Chan Ho Park, Seok Won Jung, Jung Woo Shin, Mi Ae Bae, Yoon Im Lee, Yong Tae Park, Hwa Sik Chung, and Neung Hwa Park Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea
Background/Aims: Tenofovir disoproxil fumarate (TDF) exhibits similar antiviral efficacy against treatment-naïve and lamivudine (LAM)-resistant chronic hepatitis B (CHB). However, there are few clinical reports on the antiviral effects of TDF–LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB. Methods: We investigated the antiviral efficacy of TDF monotherapy vs. TDF–LAM combination therapy in 103 patients with LAM-resistant CHB. Results: The study subjects were treated with TDF alone (n=40) or TDF–LAM combination therapy (n=63) for ≥6 months. The patients had previously been treated with TDF-based rescue therapy for a median of 30.0 months (range, 8–36 months). A virologic response (VR) was achieved in 99 patients (96.1%): 95.0% (38/40) of patients in the TDF monotherapy group and 96.8% (61/63) of patients in the TDF–LAM combination therapy group. The VR rates were not significantly different between the TDF monotherapy and TDF–LAM combination therapy groups (88.9 vs. 87.3% at month 12, and 94.4 vs. 93.7% at month 24, log-rank P=0.652). Univariate and multivariate analyses revealed that none of the pretreatment factors were significantly associated with VR. Conclusions: TDF monotherapy was as effective as TDF–LAM combination therapy for maintaining viral suppression in the vast majority of patients with LAM-resistant CHB, which suggests that TDF add-on therapy with LAM is unnecessary. (Clin Mol Hepatol 2016;22:152-159) Keywords: Tenofovir; Lamivudine; Resistance; Chronic hepatitis B
INTRODUCTION Hepatitis B virus (HBV) infection is a serious public health problem worldwide, with an estimated 2 billion infections, and a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC).1 Higher levels of HBV DNA are associated with an
increased risk for hepatocellular carcinoma (HCC) and cirrhosis.2,3 Thus, lowering of HBV DNA levels from the highest levels has been linked with a reduction in risk of both cirrhosis and HCC.4-7 Therefore, the goal of therapy in patients with chronic hepatitis B (CHB) is rapid and sustained viral suppression. Nucleos(t)ide analogues (NAs) as an important class of antiviral
Abbreviations:
Corresponding author : Neung Hwa Park
ADV, adefovir; AE, adverse event; CHB, chronic hepatitis B; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LAM, lamivudine; PCR-RFLP, polymerase chain reactionrestriction fragment length polymorphism; PVR, partial virologic response; RFMP, restriction fragment mass polymorphism; TDF, tenofovir disoproxil fumarate; VBT, virologic breakthrough; VR, virologic response
Department of Internal Medicine, Ulsan University Hospital, 877 Bangeojinsunhwando-ro, Dong-gu, Ulsan 44033, Korea Tel: +82-52-250-8845, Fax: +82-52-250-7048 E-mail: [email protected]
Received : Sep. 17, 2015 / Revised : Jan. 21, 2016 / Accepted : Feb. 11, 2016 Copyright © 2016 by The Korean Association for the Study of the Liver This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Chan Ho Park, et al. TDF-based therapy in LAM-resistant CHB
drugs have changed the treatment paradigm and prognosis of CHB. Lamivudine (LAM), the first oral antiviral agent approved to treat HBV, is safe and well tolerated, even in patients with decompensated liver cirrhosis.8 However, long-term use of NAs inevitably leads to the development of resistant HBV mutants and viral breakthrough. Resistance to LAM emerges in approximately 20% of patients after 1 year and in 70% of patients after 5 years of treatment.9 Continued treatment with LAM monotherapy in patients with LAM-resistant CHB is not recommended due to liver disease progression, including worsening of fibrosis and cirrhosis, and selection of secondary mutations.10 In addition, an increasing number of patients experience multiple NAs treatment failures, especially when they are sequentially treated with NAs that have low genetic barrier such as LAM and ADV.11-13 Therefore, for CHB patients with LAM resistance, current international guidelines recommend switching to tenofovir disoproxil fumarate (TDF), or adding on TDF.14,15 TDF achieved high rates of virologic suppression, with no development of genotypic resistance reported so far.16 TDF is recommended as first-line therapy in patients with CHB.14,15 It is also recommended for patients who have developed resistance to LAM. TDF is active in vitro against both wild-type and LAM-resistant HBV.17 Several studies have shown that the efficacy of TDF monotherapy for treating of patients with LAM-resistant CHB is currently limited to small case series or retrospective clinic-based studies.18-21 In addition, recent data show that TDF rescue therapy with LAM or emtricitabine retains significant activity for patients with LAM-resistant HBV.22-24 Fung et al. studied the efficacy of TDF/emtricitabine combination therapy compared to that of TDF monotherapy in patients with LAM-resistant CHB.25 That study showed that TDF monotherapy was as effective as the combination of TDF/emtricitabine in patients with LAM-resistant CHB. However, clinical experience with the antiviral effect of TDF-LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB is limited. In this study, we evaluated the efficacy of TDF-LAM combination therapy compared to that of TDF monotherapy in patients who developed resistance to LAM. We also determined patient-dependent or laboratory variables that predicted VR.
PATIENTS AND METHODS Patient population We reviewed the electronic medical records of patients with http://www.e-cmh.org
LAM-resistant CHB and who were treated with TDF-based rescue therapy for at least 6 months. A total of 103 patients were treated with TDF alone or a LAM combination by clinician or patient choice from December 2012 to November 2015. The study subjects were treated with TDF alone (n=40) or a TDF-LAM combination (n=63) for ≥ 6 months. All patients had hepatitis B surface antigen (HBsAg) and HBV DNA in serum for at least 6 months before the start of LAM therapy. Patients with impaired renal function (serum creatinine > 1.5 mg/dL), antibodies to hepatitis C virus, antibodies to HIV, or autoimmune hepatitis were excluded. Additional criteria for exclusion were pregnancy, lactation, and alcohol abuse (> 40 g/day ethanol). Diagnoses of chronic hepatitis and liver cirrhosis were based on liver biopsy features or on clinical, laboratory, and ultrasound data. The diagnosis of CHB was based on histological examination for 16 patients. The remaining 87 patients were clinically diagnosed. Written informed consent was obtained from all patients participating in this study. This research was approved by the Institutional Review Board at the Ulsan University Hospital.
Laboratory measurements Liver and kidney function tests were performed every 3 months during TDF rescue therapy. HBV DNA levels were quantified using the COBAS TaqMan HBV test (Roche, Branchburg, NJ, USA), which has a lower detection limit of 12 IU/mL (60 copies/mL). Specific HBV genotypes were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of the surface gene of HBV genome. The two fragments of HBV genome between nucleotide positions 2823 and 2845 and 61 and 80 were amplified using PCR, and the products were treated with restriction enzymes. Genotypic resistance to LAM was tested by restriction fragment mass polymorphism (RFMP; Genematrix, Seongnam-si, Gyeonggi, Korea assay). The RFMP assay can detect 100 copies of HBV genome per milliliter. Patients underwent surveillance for HCC every 6 months, and serial abdominal ultrasound and serum a-fetoprotein measurements were performed.
Definitions Virologic response (VR) was defined as the absence of serum HBV DNA by PCR assay (< 12 IU/mL) on two consecutive measurements during TDF treatment. HBeAg seroconversion was defined as the loss of HBeAg accompanied by detection of anti-HBe
http://dx.doi.org/10.3350/cmh.2016.22.1.152
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Clin Mol Hepatol Volume_22 Number_1 March 2016
and the absence of serum HBV DNA during treatment. Partial virologic response (PVR) was defined as a decrease in HBV DNA of
Table 1. Baseline characteristics of the studied patients (n=103)
> 1 log10 IU/mL but detectable HBV DNA after 6 months of TDFbased rescue therapy. Virologic breakthrough (VBT) was defined as a > 1 log10 IU/mL increase in serum HBV DNA from the nadir on two consecutive measurements or on the last available measurement. Safety and tolerability were evaluated by the occurrence of adverse events (AEs), serious AEs, laboratory abnormalities, discontinuation of the study drug due to AEs, or death. Specific markers of renal abnormalities included confirmed (defined as two consecutive visits) increase in serum creatinine of at least 0.5 mg/dL above the baseline value, serum phosphorus values < 2 mg/dL, and creatinine clearance < 50 mL/min.
Sex (male/female)
51 (27-90) 79/24
Liver cirrhosis, n (%)
34 (33.0)
AST (IU/L)
27.0 (15-2,431)
ALT (IU/L)
30.0 (6-3,248)
HBV DNA (log10 IU/mL)
3.61 (1.41-8.23)
HBeAg positivity, n (%)
78 (75.7)
Duration of LAM therapy (months)
33 (7-151)
Duration of TDF therapy (months)
30 (8-36)
LAM resistant mutations L180M M204V, L180M M204I, L180M M204I/V, M204I, M204V
44, 19, 12, 26, 2
Continuous variables are expressed as medians with range. AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; LAM, lamivudine;TDF, tenofovir.
Statistical analysis Serum HBV DNA (IU/mL) levels were logarithmically transformed for analysis. Continuous variables were compared using Student’s t test, and categorical variables were compared using the χ2 test. The cumulative probability rates of clinical outcomes were calculated using the Kaplan–Meier method. To identify factors predictive of outcome among the baseline variables, the clinical outcome variables were compared using the χ2 test or univariate logistic regression. Multivariate analysis was carried out using a stepwise logistic regression model. All data were analyzed using the SPSS ver. 19.0 for Windows statistical package (SPSS Inc., Chicago, IL, USA). A two-tailed P -value < 0.05 was considered significant.
RESULTS Overall clinical outcomes of TDF-based therapy The baseline characteristics of the 103 patients with CHB are shown in Table 1. All patients were genotype C2. The patients had been treated with LAM for a median of 33.0 months (range, 7–151 months) prior to TDF-based rescue treatment. All patients had LAM-resistant CHB. The known genotypic LAM mutations, L180M M204V, L180M M204I, L180M M204I/V, M204I, and M204V were detected in 44, 19, 12, 26, and two patients, respectively. Thirty-four (33.0%) patients had liver cirrhosis. Seventy-eight (75.7%) patients were HBeAg positive. The median HBV DNA level prior to TDF-based treatment was 3.61 log10 IU/mL (range, 1.41–8.23 log10 IU/mL). Thirty-four (33.0%) patients had abnormal alanine aminotransferase (ALT) levels. The subjects
154
Age (year)
were treated with TDF alone (n=40) or the TDF-LAM combination (n=63) for ≥ 6 months. The patients had been treated with TDFbased rescue therapy for a median of 30.0 months (range, 8-36 months). Mean pre-treatment HBV DNA level in HBeAg-positive CHB patients was 3.80 ± 1.58 log10 IU/mL, and it was 4.38 ± 1.51 log10 IU/mL in HBeAg-negative CHB patients. Mean pre-treatment HBV DNA level in HBeAg-negative CHB patients was similar to that in HBeAg-positive CHB patients (P =0.109). Among the 34 patients with elevated ALT levels at baseline, ALT levels were normalized in 31 patients (91.2%) during TDF-based treatment. VR was achieved in 99 patients (96.1%) during TDF-based rescue therapy. The cumulative rates of VR at 6, 12, and 24 months were 77.7%, 87.8%, and 93.9%, respectively. During TDF-based rescue therapy, 21 (20.4%) patients had PVR. Among the 78 HBeAgpositive patients, seven (9.0%) patients achieved HBeAg seroconversion during TDF-based treatment. However, no patient lost serum HBsAg during treatment. One patient in the TDF monotherapy group experienced VBT (increase in HBV DNA by 1 log10 IU/mL at 18 months of treatment) associated with documented nonadherence to medication (determined by review of medical and pharmacy records). This patient with VBT responded well to TDF monotherapy after continuation of treatment. No clinically significant AEs were observed during the TDFbased treatment. Mean creatinine level and estimated glomerular filtration rate did not change during the treatment period. Two patients (1.9%) had an increase in serum creatinine levels, but no patient had an increase in serum creatinine > 0.5 mg/dL. Mild hypophosphatemia (serum phosphorus < 2.7 mg/dL) was found in
http://dx.doi.org/10.3350/cmh.2016.22.1.152
http://www.e-cmh.org
Chan Ho Park, et al. TDF-based therapy in LAM-resistant CHB
only one patient without a change in serum creatinine.
Comparison of clinical outcomes between the TDFLAM combination and TDF monotherapy groups The baseline characteristics of the TDF monotherapy (n=40) and TDF-LAM combination groups (n=63) are shown in Table 2. There was no significant difference between the two groups except for baseline HBV DNA levels and HBeAg positivity. The patients in the TDF monotherapy group had significantly higher HBV DNA levels than the patients in the TDF-LAM combination therapy group (P
